Summary of Work: FXR is a rat nuclear receptor that is activated by micromolar amounts of farnesol, farnesoic acid, juvenile hormone (JH) III, and other metabolites of farnesyl diphosphate. These farnesoids define a metabolic shunt that together may regulate FXR-dependent gene expression. Synthetic compounds with JH biological activity such as methoprene also stimulated FXR, strengthening the notion that FXR may be related to an insect JH receptor. This hypothesis is supported by the finding that FXR is specifically activated by hydroxylated derivatives of the JH antagonist precocene, which induces premature metamorphosis. Precocene is a hepatic carcinogen that, like benzo(a)pyrene and other polyaromatic hydrocarbons, must be epoxidated to exert its toxic effects. Dimerized precocene and structurally-related chrysene derivatives also stimulated FXR as did the liver growth inducer silybin and metabolites of the anticarcinogens rotenone and limonene. FXR was also stimulated by forskolin, but neither 8-Br-cyclic AMP nor cotransfection of the catalytic subunit of PKA mimicked this effect. Analogous control of cytochrome P450 3A (CYP3A) gene expression by forskolin coupled with its induction by pharmacological doses of glucocorticoids prompted us to examine CYP3A as an FXR-regulated gene target. We found that micromolar levels of cortisol metabolites triggered FXR-dependent transcriptional activity through a specific CYP3A promoter element. Others have shown that a mevalonate-derived product is required for stimulating DNA synthesis and that farnesoids impose a block in the G1 phase of the cell cycle.